In the last few years our laboratory has provided evidence suggesting a possible role of chromosomal abnormalities in the progression of chemically induced skin tumors. Furthermore, specific non-random chromosomal alterations were identified and a temporal relationship between chromosomal abnormalities and different stages of tumor development was established. The purpose of the present proposal will be to expand those findings, to provide evidence that chromosomal abnormalities are a causal element and not an epiphenomena of tumor progression, to establish a relationship between genetic and phenotypic changes in the premalignant stages of tumor development and to investigate possible mechanisms by which chromosomal alterations play a role in carcinogenesis. In order to achieve these goals we will take advantage of two new technological developments which are particularly suitable for the study of small lesions (e.g. premalignant lesions): Interphase cytogenetics and PCR techniques. These new approaches will open new strategies to study genetic changes during tumor progression in the mouse skin model. The specific aims of this project will be: 1. To develop new methods to detect chromosomal numerical abnormalities in mouse tumors by interphase cytogenetics (in situ hybridization). 2. To establish an association between phenotypic and genotypic changes in mouse skin carcinogenesis. 3. To compare the phenotypical and genotypical stages of mouse carcinogenesis among mice with different sensitivities to tumor promotion and progression. 4. To study the expression of relevant genes in stroma-free microdissected samples of phenotypically and genotypically characterized lesions. 5. To perform a series of experiments to define the role of trisomy 6 in mouse skin carcinogenesis.